Methods For Ensuring Resuspension Of Paliperidone Palmitate Formulations

ABSTRACT

Provided are populations of syringes that respectively contain paliperidone palmitate extended release injectable suspension, wherein each of the syringes have been shipped to a destination, and the syringes were each maintained in a desired orientation during shipping of the syringe that varies from the orientation of the syringe during pre-shipping storage. The present disclosure also provides pharmaceutical products comprising a paliperidone palmitate extended-release injectable suspension within a syringe for administration to a patient suffering from schizophrenia, wherein the syringe has undergone pre-shipping storage and has been shipped, and wherein the syringe has been maintained in an orientation during the shipping that varies from the orientation of the syringe during pre-shipping storage.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Ser. No. 17/534,837,filed Nov. 24, 2021, which claims the benefit of priority to U.S.Provisional Application No. 63/237,883, filed Aug. 27, 2021, and U.S.Provisional Application No. 63/119,305, filed Nov. 30, 2020, the entiredisclosures of each of which are incorporated herein by reference.

TECHNICAL FIELD

The present disclosure pertains to methods affecting the quality ofadministration of a pharmaceutical suspension.

BACKGROUND

Antipsychotic medications are the mainstay in the treatment ofschizophrenia, schizoaffective disorder, and schizophreniform disorders.Antipsychotics were first introduced in the mid-1950s. These typical orfirst generational drugs are usually effective in controlling thepositive symptoms of schizophrenia but are less effective in moderatingthe negative symptoms or the cognitive impairment associated with thedisease. Atypical antipsychotics or second-generation drugs, typified byrisperidone and olanzapine, were developed in the 1990s, and aregenerally characterized by effectiveness against both the positive andnegative symptoms associated with schizophrenia.

Paliperidone palmitate is the palmitate ester of paliperidone(9-hydroxy-risperidone), a monoaminergic antagonist that exhibits thecharacteristic dopamine type 2 (D₂) and serotonin (5-hydroxytryptaminetype 2A) antagonism of the second generation, atypical antipsychoticdrugs. Paliperidone (9-OH risperidone) is the major active metabolite ofrisperidone. Extended release (ER) osmotic controlled release oraldelivery (OROS) paliperidone, as a tablet formulation, is marketed inthe United States (U.S.) for the treatment of schizophrenia andmaintenance of effect.

Paliperidone palmitate has been developed as a long-acting,intramuscular (i.m.), injectable aqueous nanosuspension for thetreatment of schizophrenia and other related diseases that are normallytreated with antipsychotic medications. Because of extreme low watersolubility, paliperidone esters such as paliperidone palmitate dissolveslowly after an intramuscular injection before being hydrolyzed topaliperidone and made available in the systemic circulation.

Once-monthly paliperidone palmitate injection has been developed toprovide sustained plasma concentrations of paliperidone, which maygreatly enhance compliance with dosing. Paliperidone palmitateformulated as an aqueous nanosuspension is described in U.S. Pat. Nos.6,077,843 and 6,555,544, each of which is incorporated herein byreference. In addition, dosing regimens of paliperidone palmitate fortreating patients is disclosed in U.S. Pat. Nos. 9,439,906 and10,143,693, each of which is incorporated herein by reference.

Paliperidone is currently available for therapeutic use in threeformulations: an oral extended-release formulation (INVEGA® ExtendedRelease [ER] tablets; also termed INVEGA® prolonged-release [PR]tablets), and two long-acting injectable (LAI) formulations(paliperidone palmitate 1-month injection [INVEGA SUSTENNA® or XEPLION®]and paliperidone palmitate 3-month injection [INVEGA TRINZA® orTREVICTA®]). Another paliperidone palmitate product intended foradministration once every 6 months (paliperidone palmitate 6-monthinjection) has been approved in the United States [INVEGA HAFYERA™] andEurope [BYANNLI®], with a view towards further improving adherence andconvenience.

Paliperidone palmitate suspension formulations are typically highlyconcentrated products. As a result, an important consideration is toensure complete suspension/resuspension of the product beforeadministration. To minimize the chances of incomplete administration, itis necessary for a health care professional to conduct theadministration, and to follow specific guidelines in preparation for andduring the administration. For example, the INVEGA TRINZA® labelspecifies that the syringe containing the formulation should be shakenvigorously for at least 15 seconds prior to administration in order toensure a homogeneous suspension (corresponding to instructions for use,IFU). It is also necessary to perform the injection slowly, for example,over a period of 20-30 seconds. It is also recommended that shaking isperformed while the syringe is in the tip-up position. The label forINVEGA HAFYERA™ specifies that the syringe containing the formulationshould be shaken (with the syringe tip cap pointing up) very fast for atleast 15 seconds, followed by a brief rest, and then shaken again for 15seconds.

It is possible that there may be some instances of deviation from theresuspension protocols due to human error that could lead toinsufficient resuspension and, as a result, incomplete administration ofpaliperidone palmitate suspension. A need exists for additionalstrategies for ensuring that the required resuspension of paliperidonepalmitate occurs.

SUMMARY

Provided herein are methods for improving resuspendability of apaliperidone palmitate extended-release injectable suspension within asyringe comprising maintaining the syringe in a substantially horizontalorientation during shipping of the syringe. Also provided herein aremethods for improving resuspendability of a paliperidone palmitateextended-release injectable suspension within a syringe comprisingmaintaining the syringe in an orientation during shipping that variesfrom the orientation of the syringe during pre-shipping storage, such asin a substantially horizontal orientation during shipping of the syringewhen the orientation during pre-shipping storage was not substantiallyhorizontal.

Also disclosed are methods for reducing a force required for injectionof a paliperidone palmitate extended-release injectable suspension froma syringe comprising maintaining the syringe in a substantiallyhorizontal orientation during shipping of the syringe. Also disclosedare methods for reducing a force required for injection of apaliperidone palmitate extended-release injectable suspension from asyringe comprising maintaining the syringe in an orientation duringshipping that varies from the orientation of the syringe duringpre-shipping storage, such as in a substantially horizontal orientationduring shipping of the syringe when the orientation during pre-shippingstorage was not substantially horizontal.

The present disclosure also pertains to methods for reducing thelikelihood of incomplete injection of a paliperidone palmitateextended-release injectable suspension from a syringe comprisingmaintaining the syringe in a substantially horizontal orientation duringshipping of the syringe. The present disclosure also pertains to methodsfor reducing the likelihood of incomplete injection of a paliperidonepalmitate extended-release injectable suspension from a syringecomprising maintaining the syringe in an orientation during shippingthat varies from the orientation of the syringe during pre-shippingstorage, such as in a substantially horizontal orientation duringshipping of the syringe when the orientation during pre-shipping storagewas not substantially horizontal.

Also provided are methods for improving resuspendability of apaliperidone palmitate extended-release injectable suspension within asyringe comprising maintaining the syringe in a substantially horizontalorientation during storage of the syringe. Also provided are methods forimproving resuspendability of a paliperidone palmitate extended-releaseinjectable suspension within a syringe comprising maintaining thesyringe in an orientation during shipping that varies from theorientation of the syringe during pre-shipping storage, such as in asubstantially horizontal orientation during storage of the syringe whenthe orientation during pre-shipping storage was not substantiallyhorizontal.

Also disclosed are populations of syringes that respectively containpaliperidone palmitate extended release injectable suspension, whereineach of the syringes have been shipped to a destination, and thesyringes were each maintained in a substantially horizontal orientationduring shipping of the syringe. Also disclosed are populations ofsyringes that respectively contain paliperidone palmitate extendedrelease injectable suspension, wherein each of the syringes have beenshipped to a destination, and the syringes were each maintained in anorientation during shipping that varies from the orientation of thesyringes during pre-shipping storage, such as in a substantiallyhorizontal orientation during shipping of the syringes when theorientation during pre-shipping storage was not substantiallyhorizontal.

The present disclosure also provides pharmaceutical products thatcomprise a paliperidone palmitate extended-release injectable suspensionwithin a syringe for administration to a patient suffering fromschizophrenia, wherein the syringe has undergone pre-shipping storageand has been shipped, and wherein the syringe has been maintained in anorientation during the shipping that varies from the orientation of thesyringe during pre-shipping storage.

Also disclosed are methods of treating schizophrenia comprisingadministering to a patient suffering from schizophrenia a paliperidonepalmitate extended-release injectable suspension from a syringe, whereinthe syringe has undergone pre-shipping storage and has been shipped, andwherein the syringe was maintained in an orientation during the shippingthat varied from the orientation of the syringe during pre-shippingstorage. Also disclosed are paliperidone palmitate extended-releaseinjectable suspensions for use in methods of treating schizophrenia,wherein these methods comprise administering to a patient suffering fromschizophrenia the paliperidone palmitate extended-release injectablesuspension from a syringe, wherein the syringe has undergonepre-shipping storage and has been shipped, and wherein the syringe wasmaintained in an orientation during the shipping that varied from theorientation of the syringe during pre-shipping storage. Also disclosedis the use of a paliperidone palmitate extended-release injectablesuspension in the manufacture of a medicament for treatingschizophrenia, wherein the paliperidone palmitate extended-releaseinjectable suspension is prepared for administration from a syringe,wherein the syringe has undergone pre-shipping storage and has beenshipped, and wherein the syringe was maintained in an orientation duringthe shipping that varied from the orientation of the syringe duringpre-shipping storage.

In embodiments of the present disclosure, the paliperidone palmitateextended-release injectable suspension is selected from the groupconsisting of PP3M and PP6M. In one embodiment, the paliperidonepalmitate extended-release injectable suspension is PP3M. In oneembodiment, the paliperidone palmitate extended-release injectablesuspension is PP6M.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1F depict force injection profiles for process performancequalification (PPQ) batches of PP6M that were respectively stored in oneof five different spatial orientations.

FIGS. 2A-2D provide injection force curves for syringes subjected tovibration experiments while in a horizontal or tip down orientation.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The presently disclosed inventive subject matter may be understood morereadily by reference to the following detailed description taken inconnection with the accompanying examples, which form a part of thisdisclosure. It is to be understood that these inventions are not limitedto the specific formulations, methods, or parameters described and/orshown herein, and that the terminology used herein is for the purpose ofdescribing particular embodiments by way of example only and is notintended to be limiting of the claimed inventions.

The entire disclosures of each patent, patent application, andpublication cited or described in this document are hereby incorporatedherein by reference.

As employed above and throughout the disclosure, the following terms andabbreviations, unless otherwise indicated, shall be understood to havethe following meanings.

In the present disclosure the singular forms “a,” “an,” and “the”include the plural reference, and reference to a particular numericalvalue includes at least that particular value, unless the contextclearly indicates otherwise. Thus, for example, a reference to “aformulation” is a reference to one or more of such formulation andequivalents thereof known to those skilled in the art, and so forth.Furthermore, when indicating that a certain element “may be” X, Y, or Z,it is not intended by such usage to exclude in all instances otherchoices for the element.

When values are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms anotherembodiment. In general, use of the term “about” indicates approximationsthat can vary depending on the desired properties sought to be obtainedby the disclosed subject matter and is to be interpreted in the specificcontext in which it is used, based on its function. In some embodiments,“about X” (where X is a numerical value) refers to +10% of the recitedvalue, inclusive. For example, the phrase “about 8” can refer to a valueof 7.2 to 8.8, inclusive. This value may include “exactly 8”. Wherepresent, all ranges are inclusive and combinable. For example, when arange of “1 to 5” is recited, the recited range should be construed asoptionally including ranges “1 to 4”, “1 to 3”, “1-2”, “1-2 & 4-5”, “1-3& 5”, and the like. In addition, when a list of alternatives ispositively provided, such a listing can also include embodiments whereany of the alternatives may be excluded. For example, when a range of “1to 5” is described, such a description can support situations wherebyany of 1, 2, 3, 4, or 5 are excluded; thus, a recitation of “1 to 5” maysupport “1 and 3-5, but not 2”, or simply “wherein 2 is not included.”

It should be understood that references herein to methods of treatment(e.g., methods of treating schizophrenia) using one or more compounds orformulations thereof (e.g., paliperidone palmitate extended releaseinjectable suspension) should also be interpreted as references to:

-   -   one or more compounds or formulations thereof (e.g. paliperidone        palmitate extended-release injectable suspension) for use in        methods of treating, e.g., schizophrenia; and/or    -   the use of one or more compounds of formulations thereof (e.g.,        a paliperidone palmitate extended-release injectable suspension)        in the manufacture of a medicament for treating, e.g.,        schizophrenia.

As described above, resuspension protocols exist in order to ensurecomplete administration of paliperidone palmitate injectable suspension.Although prescribed paliperidone palmitate formulations include clearlabel instructions concerning the correct procedure for preparing theformulations for administration and for the mode in which the injectionitself should be performed, it is possible that health care personnelwho are charged with following the specified procedures may not do so ina manner that ensures adequate resuspension of paliperidone palmitateand thereby delivery of the prescribed dosage to the patient in need.

The present inventors have surprisingly discovered that varying theorientation of the syringes that contain the paliperidone palmitatesuspension during the shipping process relative to the orientation ofthe syringes during a pre-shipping storage period influences theresuspendability of the drug product in preparation for administration.In particular, it has been found that maintaining the syringes in anorientation during shipping that varies from the orientation of thesyringe during pre-shipping storage, such as in a substantiallyhorizontal orientation during shipping, for example, as opposed to thetraditional tip-down orientation when the syringes were also storedprior to shipping in a tip-down orientation, improves theresuspendability of the paliperidone palmitate, and thereby improves thelikelihood that complete administration of the prescribed dosage occurs.Therefore, the present discovery has the effect of mitigating humanerror or other causes of deviation from the prescribed resuspensionprotocol (e.g., governing the type and duration of shaking) that isintended to ensure adequate resuspension of the paliperidone palmitate.As a result of the improvement in the resuspension of drug, certainbenefits accrue, such as the reduction in the amount of force requiredfor administration, and, as a general matter, the chances of incompleteadministration are reduced. This can also improve resuspension byreducing the force of the shaking that is required for resuspension. Thefact that the chances of incomplete administration are reduced means, inturn, that the risk of a patient receiving a lower-than-intended dose ofpaliperidone palmitate is also reduced. This means that in instances ofdeviation from the prescribed resuspension protocol, a patient sufferingfrom schizophrenia who is administered paliperidone palmitateextended-release injectable suspension from a syringe which has, forexample, been maintained in an orientation during shipping that variesfrom the orientation of the syringe during pre-shipping storage, such asin a substantially horizontal orientation during shipping, is lesslikely to receive a lower-than-intended dose than a patient who has beenadministered paliperidone palmitate extended-release injectablesuspension from a syringe which has, for example, been maintained in thetraditional tip-down orientation during shipping. Thus, theadministration of a paliperidone palmitate extended-release injectablesuspension from a syringe which has, for example, been maintained in anorientation during shipping that varies from the orientation of thesyringe during pre-shipping storage, such as in a substantiallyhorizontal orientation during shipping, represents an importantcontribution to the field of schizophrenia therapy.

Accordingly, provided herein are methods for improving resuspendabilityof a paliperidone palmitate extended-release injectable suspensionwithin a syringe comprising maintaining the syringe in a substantiallyhorizontal orientation during shipping of the syringe. The presentdisclosure also embraces methods for reducing the likelihood ofincomplete injection of a paliperidone palmitate extended releaseinjectable suspension from a syringe, comprising maintaining the syringein a substantially horizontal orientation during shipping of thesyringe. Also provided herein are methods for improving resuspendabilityof a paliperidone palmitate extended-release injectable suspensionwithin a syringe comprising maintaining the syringe in an orientationduring shipping that varies from the orientation of the syringe duringpre-shipping storage, such as in a substantially horizontal orientationduring shipping of the syringe when the orientation during pre-shippingstorage was not substantially horizontal. The present disclosure alsoembraces methods for reducing the likelihood of incomplete injection ofa paliperidone palmitate extended release injectable suspension from asyringe, comprising maintaining the syringe in an orientation duringshipping that varies from the orientation of the syringe duringpre-shipping storage, such as in a substantially horizontal orientationduring shipping of the syringe when the orientation during pre-shippingstorage was not substantially horizontal.

In embodiments of the present disclosure, the paliperidone palmitateextended-release injectable suspension is selected from the groupconsisting of PP3M and PP6M. In one embodiment, the paliperidonepalmitate extended-release injectable suspension is PP3M. In oneembodiment, the paliperidone palmitate extended-release injectablesuspension is PP6M.

Paliperidone esters are antipsychotic agents belonging to the chemicalclass of benzisoxazole derivatives, which contains a racemic mixture of(+)- and (−)-paliperidone, which are described in U.S. Pat. No.5,254,556 (incorporated herein by reference). The chemical name forpaliperidone palmitate is(±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyrido[1,2-c]pyrimidin-9-ylhexadecanoate. The structural formula is:

Paliperidone esters may be formulated with pharmaceutical excipientsinto injectable dosage forms as described in U.S. Pat. Nos. 5,254,556and 6,077,843 both of which are incorporated herein by reference.Injectable formulations may be formulated in aqueous carriers.

The paliperidone palmitate extended-release injectable suspension maybe, for example, a commercially available formulation that is intendedfor administration to a subject once every three months, once every sixmonths, or some other interval.

Commercially available formulations that are for administration onceevery three months include INVEGA TRINZA® or TREVICTA®. See also U.S.Pat. No. 10,143,693 incorporated herein by reference. In the presentdisclosure, “PP3M” refers to a paliperidone palmitate extended-releaseinjectable suspension or other type of formulation having an amount ofpaliperidone palmitate suitable for a dosing interval of aboutthree-months. For example, “PP3M” can refer to a paliperidone palmitateextended-release injectable suspension having a dosing interval of aboutthree-months.

Commercially available formulations that are for administration onceevery six months include INVEGA HAFYERA™ in the United States. Aformulation for administration once every six months has receivedmarketing authorization in Europe under the trade name BYANNLI®. In thepresent disclosure, “PP6M” refers to a paliperidone palmitateextended-release injectable suspension or other type of formulationhaving an amount of paliperidone palmitate suitable for a dosinginterval of about six-months. For example, “PP6M” can refer to apaliperidone palmitate extended-release injectable suspension having adosing interval of about six-months. PP6M will typically be providedwith a dose in the range of from about 1000 mg to about 1600 mg ofpaliperidone palmitate to provide a sustained therapeutic concentrationof paliperidone over the six-month dosing interval. Preferably, the PP6Mwill be provided in dose strengths of about 1092 mg or about 1560 mgpaliperidone palmitate. The drug product hydrolyzes to the activemoiety, paliperidone, resulting in dose strengths of about 700 mg eq. or1000 mg eq. of paliperidone, respectively.

PP6M is preferably provided in a prefilled syringe(cyclic-olefin-copolymer) prefilled with either 700 mg eq. (3.5 mL) or1000 mg eq. (5.0 mL) paliperidone (as 1092 mg or 1560 mg paliperidonepalmitate, respectively) with a plunger stopper, a plunger rod, and tipcap (bromobutyl rubber), a backstop, and a needle, preferably a thinwalled 20 gauge (G), 1.5-inch safety needle.

PP3M will typically be provided with a dose in the range of from about270 mg to about 825 mg of paliperidone palmitate to provide a sustainedtherapeutic concentration of paliperidone over the three-month dosinginterval. Preferably, the PP3M will be provided in dose strengths ofabout 273, 410, 546, or 819 mg paliperidone palmitate. The drug producthydrolyzes to the active moiety, paliperidone, resulting in dosestrengths of about 175, 263, 350, or 525 mg eq. of paliperidone,respectively.

PP3M is preferably provided in a prefilled syringe(cyclic-olefin-copolymer) prefilled with about 175 mg eq. to about 525mg eq. with a plunger stopper, a plunger rod, and tip cap (bromobutylrubber), a backstop, and a needle, preferably a thin walled 20 gauge(G), 1.5-inch safety needle, or a thin walled 22 gauge (G), 1-inchsafety needle.

In certain embodiments, PP3M and PP6M can have the same formulation, anddiffer in terms of the total volume of the suspension formulation thatis housed within respective syringes. The paliperidone palmitatesuspension that is used pursuant to the present methods may contain, inabsolute amounts, about 250 to about 1600 mg of paliperidone palmitate.The amount of paliperidone palmitate in the suspension may be, forexample, 273, 410, 546, or 819 mg. In certain embodiments, the amount ofpaliperidone palmitate in the suspension may be 1092 or 1560 mg.

In certain embodiments, a 3-month (PP3M) formulation has averageparticle sizes of less than about 20 μm to about 1 μm. In otherembodiments, the particles have an average particle size (d50) of fromabout 5 μm to about 15 μm; from about 3 μm to about 10 μm; or from about5 μm to about 9 μm. The d90 may be about 50 μm; from about 10 μm toabout 30 μm; or from about 10 μm to about 20 μm. The d10 may be fromabout 1 μm to about 10 μm, or about 1 μm to about 5 μm.

In certain embodiments, a 6-month (PP6M) formulation has an averageparticle size of less than about 30 μm to about 1 μm; or about 20 μm toabout 1 μm. In other embodiments, the particles have an average particlesize (d50) of from about 3 μm to about 25 μm; from about 5 μm to about15 μm; from about 3 μm to about 10 μm; or from about 5 μm to about 9 μm.The d90 may be 60 μm; or about 50 μm; from about 10 μm to about 30 μm;or from about 10 μm to about 20 μm. The d10 may be from about 1 μm toabout 15 μm; from about 1 μm to about 10 μm; or about 1 μm to about 5μm.

As used herein, d10: the portion of particles with diameters smallerthan this value is 10%; d50: the portion of particles with diameterssmaller than this value are 50%; d90: the portion of particles withdiameters smaller than this value is 90%; when measured by art-knownconventional techniques, such as sedimentation field flow fractionation,photon correlation spectroscopy or disk centrifugation.

Suitable aqueous nanoparticle formulations are described in U.S. Pat.No. 6,555,544 which is incorporated herein by reference. In someembodiments, the formulation comprises micro particles, a surfactant, asuspending agent, and optionally one or more additional ingredientsselected from the group consisting of preservatives, buffers and anisotonizing agent.

Useful surface modifiers for paliperidone palmitate formulations arebelieved to include those that physically adhere to the surface of theactive agent but do not chemically bond thereto. Suitable surfacemodifiers can be selected from known organic and inorganicpharmaceutical excipients. Such excipients include various polymers, lowmolecular weight oligomers, natural products and surfactants. Preferredsurface modifiers include nonionic and anionic surfactants.Representative examples of excipients include gelatin, casein, lecithin(phosphatides), gum acacia, cholesterol, tragacanth, stearic acid,benzalkonium chloride, calcium stearate, glyceryl monostearate,cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitanfatty acid esters, e.g., the commercially available TWEENs™,polyethylene glycols, polyoxyethylene stearates, colloidal silicondioxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose phtalate, noncrystalline cellulose,magnesium aluminate silicate, triethanolamine, polyvinyl alcohol (PVA),poloxamers, tyloxapol and polyvinylpyrrolidone (PVP). Most of theseexcipients are described in detail in the Handbook of PharmaceuticalExcipients, published jointly by the American Pharmaceutical Associationand The Pharmaceutical Society of Great Britain, the PharmaceuticalPress, 1986. The surface modifiers are commercially available and/or canbe prepared by techniques known in the art. Two or more surfacemodifiers can be used in combination.

Particularly preferred surface modifiers include polyvinylpyrrolidone;tyloxapol; poloxamers, such as PLURONIC™ F68, F108 and F127 which areblock copolymers of ethylene oxide and propylene oxide available fromBASF; poloxamines, such as TETRONIC™ 908 (T908) which is atetrafunctional block copolymer derived from sequential addition ofethylene oxide and propylene oxide to ethylenediamine available fromBASF; dextran; lecithin; Aerosol OT™ (AOT) which is a dioctyl ester ofsodium sulfosuccinic acid available from Cytec Industries; DUPONOL™ Pwhich is a sodium lauryl sulfate available from DuPont; TRITON™ X-200which is an alkyl aryl polyether sulfonate available from Rohm and Haas;TWEEN™ 20, 40, 60 and 80 which are polyoxyethylene sorbitan fatty acidesters available from ICI Speciality Chemicals; SPAN™ 20, 40, 60 and 80which are sorbitan esters of fatty acids; ARLACEL™ 20, 40, 60 and 80which are sorbitan esters of fatty acids available from Hercules, Inc.;CARBOWAX™ 3550 and 934 which are polyethylene glycols available fromUnion Carbide; CRODESTA™ F110 which is a mixture of sucrose stearate andsucrose distearate available from Croda Inc.; CRODESTA™ SL-40 which isavailable from Croda, Inc.; hexyldecyl trimethyl ammonium chloride(CTAC); bovine serum albumin, and SA90HCO which has the formula asfollows:

C₁₈H₁₇CH₂(CON(CH₃)CH₂(CHOH)₄CH₂OH)₂.

The surface modifiers which have been found to be particularly usefulinclude tyloxapol and a poloxamer, preferably, Pluronic™ F108 andPluronic™ F68.

Pluronic™ F108 corresponds to poloxamer 338 and is the polyoxyethylene,polyoxypropylene block copolymer that conforms generally to the formulaHO[CH₂CH₂O]_(x)[CH(CH₃)CH₂O]_(y)[CH₂CH₂O]_(z)H in which the averagevalues of x, y and z are respectively 128, 54 and 128. Other commercialnames of poloxamer 338 are Hodag NONIONIC™ 1108-F available from Hodag,and SYNPERONIC™ PE/F108 available from ICI Americas.

The optimal relative amount of paliperidone palmitate and the surfacemodifier depends on various parameters. The optimal amount of thesurface modifier can depend, for example, upon the particular surfacemodifier selected, the critical micelle concentration of the surfacemodifier if it forms micelles, the surface area of the antipsychoticagent, etc. The specific surface modifier preferably is present in anamount of about 0.1 to about 1 mg per square meter surface area of thepaliperidone palmitate. It is preferred in the case of paliperidonepalmitate (9-hydroxyrisperidone palmitate) to use PLURONIC™ F108 as asurface modifier, a relative amount (w/w) of both ingredients ofapproximately 6:1 is preferred.

The particles of a paliperidone palmitate suspension can be prepared bya method comprising the steps of dispersing paliperidone palmitate in aliquid dispersion medium and applying mechanical means in the presenceof grinding media to reduce the particle size of the antipsychotic agentto an effective average particle size. The particles can be reduced insize in the presence of a surface modifier. Alternatively, the particlescan be contacted with a surface modifier after attrition.

A general procedure for preparing the particles of a paliperidonepalmitate suspension may include (a) obtaining paliperidone palmitate;(b) adding the paliperidone palmitate to a liquid medium to form apremix; and (c) subjecting the premix to mechanical means in thepresence of a grinding medium to reduce the effective average particlesize.

The paliperidone palmitate may be prepared using techniques known in theart. It is preferred that the particle size of the paliperidonepalmitate be less than about 100 μm as determined by sieve analysis. Ifthe particle size of the paliperidone palmitate is greater than about100 μm, then it is preferred that the particles of paliperidonepalmitate be reduced in size to less than 100 μm.

The paliperidone palmitate can then be added to a liquid medium in whichit is essentially insoluble to form a premix. The concentration ofpaliperidone palmitate in the liquid medium (weight by weightpercentage) can vary widely and depends on the selected antipsychoticagent, the selected surface modifier and other factors. Suitableconcentrations of paliperidone palmitate in compositions vary from about0.10% to about 60%, preferably is from about 0.5% to about 30%, and morepreferably, is approximately 7% (w/v). For PP3M, it is preferred to usea concentration of about 200 mg eq. of paliperidone per mL or about 312mg of paliperidone palmitate per mL. For PP6M, it is preferred to use aconcentration of about 200 mg eq. of paliperidone per mL or about 312 mgof paliperidone palmitate per mL.

Another exemplary procedure involves the addition of a surface modifierto the premix prior to its subjection to mechanical means to reduce theeffective average particle size. The concentration of the surfacemodifier (weight by weight percentage) can vary from about 0.1% to about90%, preferably from about 0.5% to about 80%, and more preferably isapproximately 7% (w/v).

The premix can be used directly by subjecting it to mechanical means toreduce the effective average particle size in the dispersion to thedesired particle size. It is preferred that the premix be used directlywhen a ball mill is used for attrition. Alternatively, the antipsychoticagent and, optionally, the surface modifier, can be dispersed in theliquid medium using suitable agitation such as, for example, a rollermill or a Cowles type mixer, until a homogeneous dispersion is achieved.

The mechanical means applied to reduce the effective average particlesize of the antipsychotic conveniently can take the form of a dispersionmill. Suitable dispersion mills include a ball mill, an attritor mill, avibratory mill, a planetary mill, media mills-such as a sand mill and abead mill. A media mill is preferred due to the relatively shortermilling time required to provide the desired reduction in particle size.For media milling, in some embodiments, the apparent viscosity of thepremix preferably is anywhere between about 0.1 Pa s and about 1 Pa s.In some embodiments, for ball milling, the apparent viscosity of thepremix preferably is anywhere between about 1 mPa s and about 100 mPa s.

The grinding media for the particle size reduction step can be selectedfrom rigid media preferably spherical or particulate in form having anaverage size less than about 3 mm and, more preferably, less than about1 mm. Such media desirably can provide the particles of the inventionwith shorter processing times and impart less wear to the millingequipment. The selection of the material for the grinding media isbelieved not to be critical. However, about 95% ZrO stabilized withmagnesia, zirconium silicate, and glass grinding media provide particleswhich are acceptable for the preparation of pharmaceutical compositions.Further, other media, such as polymeric beads, stainless steel, titania,alumina and about 95% ZrO stabilized with yttrium, are useful. Preferredgrinding media have a density greater than about 2.5 g/cm³ and includeabout 95% ZrO stabilized with magnesia and polymeric beads.

The attrition time can vary widely and depends primarily upon theparticular mechanical means and processing conditions selected. Forrolling mills, processing times of up to two days or longer may berequired for smaller size particles.

The particles should be reduced in size at a temperature which does notsignificantly degrade the antipsychotic agent. Processing temperaturesof less than about 30° C. to about 40° C. are ordinarily preferred. Ifdesired, the processing equipment may be cooled with conventionalcooling equipment. The method is conveniently carried out underconditions of ambient temperature and at processing pressures which aresafe and effective for the milling process.

The surface modifier, if it was not present in the premix, is typicallyadded to the dispersion after attrition in an amount, for example, asdescribed for the premix above. Thereafter, the dispersion can be mixedby, for example, shaking vigorously. Optionally, the dispersion can besubjected to a sonication step using, for example, an ultrasonic powersupply.

Aqueous compositions may further comprise a suspending agent and abuffer, and optionally one or more of a preservative and an isotonizingagent. Particular ingredients may function as two or more of theseagents simultaneously, e.g. behave like a preservative and a buffer, orbehave like a buffer and an isotonizing agent.

Suitable suspending agents (also referred to as physical stabilizers)for use in the aqueous suspensions according to the present inventionare cellulose derivatives, e.g. methyl cellulose, sodium carboxymethylcellulose and hydroxypropyl methyl cellulose, polyvinylpyrrolidone,alginates, chitosan, dextrans, gelatin, polyethylene glycols,polyoxyethylene- and polyoxy-propylene ethers. Preferably sodiumcarboxymethyl cellulose is used in a concentration of about 0.5 to about2%, most preferably about 1% (w/v).

Suitable wetting agents preferred from the listed surfactant for use inthe aqueous suspensions according to the present invention arepolyoxyethylene derivatives of sorbitan esters, e.g. polysorbate 20 andpolysorbate 80, lecithin, polyoxyethylene- and polyoxypropylene ethers,sodium deoxycholate. Preferably polysorbate 20 is used in aconcentration of about 0.5% to about 3%, more preferably about 0.5% toabout 2%, most preferably about 1.1% (w/v).

Suitable buffering agents are salts of weak acids and should be used inamount sufficient to render the dispersion from about pH 6.0 to basic.Preferably, the pH is in a range of from about 6.0 to about 9.0; or inthe range of from about 6.0 to about 8.0; or about 6.5 to about 7.5. Forexample, the pH is in the range of about 6.0 to about 6.5; or from about6.5 to about 7.0; or from about 7.0 to about 7.5; or from about 7.5 toabout 8.0; or from about 8.0 to about 8.5; or from about 8.5 to about9.0. Particularly preferred is the use of a mixture of disodium hydrogenphosphate (anhydrous) (typically about 0.9% (w/v)) and sodium dihydrogenphosphate monohydrate (typically about 0.6% (w/v)). This buffer alsorenders the dispersion isotonic and, in addition, less prone toflocculation of the ester suspended therein.

Preservatives can include antimicrobials and anti-oxidants which can beselected from the group consisting of benzoic acid, benzyl alcohol,butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, agallate, a hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol,benzethonium chloride, myristyl-gamma-piccolinium chloride,phenylmercuric acetate and thimerosal. In particular, it is benzylalcohol which can be used in a concentration up to about 2% (w/v),preferably up to about 1.5% (w/v).

Isotonizing agents are, for example, sodium chloride, dextrose,mannitol, sorbitol, lactose, sodium sulfate. The suspensionsconveniently comprise from about 0% to about 10% (w/v) isotonizingagent. Mannitol may be used in a concentration from about 0% to about 7%more preferably, however, from about 1% to about 3% (w/v), especiallyfrom about 1.5% to about 2% (w/v) of one or more electrolytes are usedto render the suspension isotonic, apparently because ions help toprevent flocculation of the suspended ester. In particular, electrolytesof the buffer serve as isotonizing agent.

A particularly desirable feature for an injectable formulation relatesto the ease with which it can be administered. In particular such aninjection should be feasible using a needle as fine as possible in aspan of time which is as short as possible. This can be accomplishedwith the aqueous suspensions of the present invention by maintainingcertain viscosities that can be easily taken up in a syringe (e.g., froma vial), and injected through a fine needle. For example, in someembodiments the viscosity is below about 75 mPa s, or below about 60 mPas at room temperature. For PP3M, a 22G, 1 ½ inch needle, or a 22G, 1inch needle is typically used. For PP6M, a 20G, 11₂ inch needle istypically used.

Ideally, aqueous suspensions for use in accordance with the presentmethods include as much prodrug as can be tolerated so as to keep theinjected volume to a minimum, and as little of the other ingredients aspossible.

In particular for PP3M or PP6M, the composition may comprise, or consistessentially of, (a) from about 200 to about 500 mg/mL of prodrug; (b)from about 2 to about 25 mg/mL of wetting agent; (c) from about 2.5 toabout 50 mg/mL of one or more buffering agents; (d) from about 25 toabout 150 mg/mL of a suspending agent; (e) optionally up to about 2%(w/v) preservatives; and (f) water q.s. ad 100%. Typically, the PP3M orPP6M composition has a pH of from about 6.0 to about 8.0, preferablyabout a pH of from 6.5 to about 7.5.

In other embodiments, for PP3M or PP6M, the composition may comprise orconsist essentially of, (a) from about 250 to about 400 mg/mL ofprodrug; (b) from about 5 to about 20 mg/mL of wetting agent; (c) fromabout 5 to about 25 mg/mL of one or more buffering agents; (d) fromabout 50 to about 100 mg/mL of a suspending agent; (e) optionally up toabout 2% (w/v) preservatives; and (f) water q.s. ad 100%.

In other embodiments, for PP3M or PP6M, the composition may comprise, orconsist essentially of, (a) from about 280 to about 350 mg/mL ofprodrug; (b) from about 8 to about 12 mg/mL of wetting agent; (c) fromabout 5 to about 15 mg/mL of one or more buffering agents; (d) fromabout 65 to about 85 mg/mL of a suspending agent; (e) optionally up toabout 2% (w/v) preservatives; and (f) water q.s. ad 100%.

The active ingredient in PP3M or PP6M comprises paliperidone palmitate(about 312 mg/mL). In certain preferred embodiments, the inactiveingredients in PP3M or PP6M will be polysorbate 20 (about 10 mg/mL),polyethylene glycol 4000 (about 75 mg/mL), citric acid monohydrate(about 7.5 mg/mL), sodium dihydrogen phosphate monohydrate (about 6mg/mL), sodium hydroxide (about 5.4 mg/mL) and water for injection. Anexemplified PP3M is disclosed in Example 1. An exemplified PP6M isdisclosed in Example 2.

The present methods include maintaining a syringe containing apaliperidone palmitate extended-release injectable suspension in asubstantially horizontal orientation during shipping of the syringe. Thepresent methods also include maintaining a syringe containing apaliperidone palmitate extended-release injectable suspension in anorientation during shipping that varies from the orientation of thesyringe during pre-shipping storage, such as in a substantiallyhorizontal orientation during shipping of the syringe when theorientation during pre-shipping storage was not substantiallyhorizontal.

Regardless of the particular orientation of a syringe duringpre-shipping storage thereof, in accordance with the present methods,varying the orientation of the syringe during shipping following suchpre-shipping storage can mean maintaining the syringe in a shippingorientation that represents an angular deviation from the orientationduring storage of about 45 to about 135 degrees. For example, theorientation of the syringe during shipping may vary from the orientationof the syringe during pre-shipping storage by about 45, 50, 55, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, or 135degrees.

For example, the orientation of the syringe during shipping may besubstantially horizontal. This is especially suitable when theorientation of the syringe during pre-shipping storage was tip-up ortip-down (wherein the “tip” of the syringe refers to the portion of thesyringe to which a needle is attached for purposes of injection). Asubstantially horizontal orientation may refer to an orientation inwhich the syringe is at an angle that is closer to 0° than to 90°relative to the applicable reference point, such as the ground, normalto the force of gravity, or the floor of the vehicle in which thesyringe is shipped. For example, a substantially horizontal orientationmay refer to an orientation that is at 0, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 3, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44 degreesrelative to the pertinent reference point.

In other embodiments, the orientation of the syringe during shipping maybe substantially tip up. This represents a suitable shipping orientationwhen the orientation of the syringe during pre-shipping storage wastip-down or substantially horizontal. A tip up orientation may refer toan orientation in which the syringe is at an angle such that the tip iscloser to 90° than to 0° relative to the applicable reference point,such as the ground, normal to the force of gravity, or the floor of thevehicle in which the syringe is shipped. For example, a tip uporientation may refer to an orientation that is 90, 89, 88, 87, 86, 85,84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67,66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49,48, 47, or 46 degrees relative to the pertinent reference point.

In other embodiments, the orientation of the syringe during shipping maybe substantially tip down. This represents a suitable shippingorientation when the orientation of the syringe during pre-shippingstorage was tip-up or substantially horizontal. A tip down orientationmay refer to an orientation wherein the syringe is flipped 180° relativeto one of the tip up orientations described herein.

Regardless of the particular orientation during shipping, “maintaining”an orientation preferably means that the acceptable angle(s) apply forthe majority of the time during the shipping process. Ideally, when asubstantially horizontal orientation during shipping is desired, thesyringe is maintained during shipping at an angle that is always normalto the force of gravity, but, as a practical matter, variations inorientation during shipping inevitably occur due to changes in theorientation of the vehicle in which the syringe is shipped. For example,the orientation of a syringe may be normal to the force of gravity whena truck onto which the syringe is loaded for shipping is at rest on flattopography, but this orientation changes when the truck climbs ordescends a hill during the shipping process. Thus, a useful referencepoint can be the floor of the shipping vehicle rather than the force ofgravity, and preferably the syringe is maintained at an orientation thatis substantially parallel to the floor of the vehicle during shipping.

Maintaining a particular orientation during shipping of the syringe maycomprise loading the syringe onto a shipping vehicle in the desiredorientation, monitoring the syringe during shipping to confirmmaintenance of the desired orientation, or both. Loading the syringeonto a shipping vehicle in the desired orientation refers to the mannerin which the package that houses the syringe is placed onto the shippingvehicle, with the intention that the orientation at the time that thepackage is placed onto the shipping vehicle is not deliberately changedduring the shipping process. Monitoring the syringe during shipping toconfirm maintenance of the desired orientation can include direct orindirect observation by a person, by an automatic system that isprogrammed to confirm compliance with the desired orientation, or acombination of these. Direct observation by a person can include visualinspection by a person of the packaging that houses the syringe.Indirect observation can include the use of a sensor that is attached toor otherwise enables monitoring of the syringe, the package containingthe syringe, or both. The sensor can, for example, be capable ofacquiring and transmitting information concerning the orientation of thesyringe and/or package to a human observer, who determines if thetransmitted information indicates that the syringe is being maintainedin the required orientation during the shipping process. The sensors canalso be capable of conveying an alarm or some other notification if theorientation of the container or package has deviated from theappropriate orientation, for example, if the container/package hasshifted during shipping. In one embodiment, the particular orientation,or the desired orientation, is substantially horizontal.

Human monitors or sensors that can detect information concerning theorientation of the syringe can provide a direct determination of theorientation of the syringe, or can do so indirectly, by determining theorientation of the package housing the syringe. For example, markings onthe outside of the package can provide a visual cue to a sensor or ahuman monitor that indicates a corresponding orientation of the syringethat is housed within the package. Accordingly, the syringe may behoused in a container (package) comprising an outer surface that bearsinstructions or markings that enable the maintenance of the containerduring shipping in an orientation that corresponds to the orientation ofthe syringe that is desired (e.g., a substantially horizontalorientation). In some embodiments, the instructions may be provided inappropriate languages, depending on the origin, personnel that areconducting the shipping, and destination of the syringe. In someembodiments, the markings on the outer surface of the container may bean arrow indicating which side of the container should be orientated atthe top, at the bottom, or to the side, as appropriate. When there iscompliance with the instructions or markings, a syringe that is housedwithin the container will be oriented correctly in accordance with thepresent methods.

The shipping of the syringe may occur by any required means oftransportation, such as airship (airplane, helicopter, or the like),truck, boat, railroad, or by any combination of these means that mayoccur from the point of shipping from the drug manufacturing facility tothe health care facility where administration occurs. The total durationof the shipping can be any period that is required to convey the syringefrom the initial storage location to a second location, such as to ahealth care facility. For example, the duration of the shipping may beabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 hours. Theshipping process can involve periods of time during which the syringe isbeing conveyed, with one or more intervals during which the syringe isnot being conveyed, such as at a temporary storage depot prior to afurther interval of conveyance. For purposes of the present disclosure,the duration of the shipping can, but does not necessarily need to,refer to the total amount of time that elapses from removal of thesyringe from the initial storage facility following manufacture, untilthe arrival at the facility where administration takes place.

The present methods may further comprise, subsequent to the shipping ofthe syringe and prior to administration of the drug suspension,maintaining the syringe at a storage location in a deliberately selectedorientation, such as in a substantially horizontal orientation. In thiscontext, because the floor of a storage facility is likely to be leveland thereby normal to the force of gravity, the substantially horizontalorientation can preferably refer to an angle that is substantiallyparallel to the floor of the storage facility. This can mean that theangle between the long axis of the syringe and the floor of the storagefacility is preferably less than about 20, 15, 10, 9, 8, 7, 6, 5, 4, 3,2, or 1 degree.

As described above, the present methods facilitate and improveresuspension of the paliperidone palmitate syringe contents. Oneintended outcome of resuspending the paliperidone palmitate particles isthe reduction or removal of residue representing non-resuspendedpaliperidone palmitate within the tip of the syringe. To the extent thatresuspension is incomplete, non-resuspended paliperidone palmitate canremain within the tip of the syringe following administration, andthereby represents undelivered drug and is an indicator of an incompleteadministration. Minimizing the amount of residue representingnon-resuspended paliperidone palmitate that remains within the syringetip following administration represents a further beneficial outcome ofthe presently disclosed methods. For example, in accordance with thepresent methods, the syringe tip can contain no more than about 3, 2.5,2, 1.5, 1, or 0.5 mm of residue representing non-resuspendedpaliperidone palmitate following administration. In some embodiments,the syringe tip contains about 3, 2.8, 2.6, 2.5, 2.4, 2.2., 2.1, 2, 1.9,1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4,0.3, 0.2, 0.1, or zero mm of residue representing non-resuspendedpaliperidone palmitate following administration.

The syringe may be of any type and equipped with any needle that aresuitable for storage and administration of the paliperidone palmitateinjectable suspension. For example, the syringe may have a capacity of1, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 2.8, 3, 3.25, 3.5, 3.75, 4,4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, or 7 mL. Insome embodiments, the syringe has a capacity of 1, 2.25, 2.8, or 3 mL,and includes a 22 gauge needle that is 1 or 1.5 inches long. In someembodiments, the syringe has a capacity of 5 mL and includes a 20 gaugeneedle that is 1.5 inches long. With respect to any of the presentlydisclosed inventions, the volume of the paliperidone palmitateinjectable suspension with a syringe may be, for example, 1, 1.25, 1.5,1.75, 2.0, 2.25, 2.5, 2.75, 2.8, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75,5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, or 7 mL.

The present methods can further comprise the step of administering thesuspension from the syringe (i.e., that had been maintained in a desiredorientation during shipping) to a patient. In some embodiments, thedesired orientation is substantially horizontal. Administration of thesuspension should be performed, for example, in accordance with theprotocols described on the label of the aforementioned commerciallyavailable paliperidone palmitate extended release injectable suspensionproducts. Although the present methods mitigate certain instances offailure by health care personnel to adhere precisely to the recommendedsteps prior to and during administration of paliperidone palmitateextended release injectable suspension, it is still advisable for theadministration of the suspension from the syringe according to thepresent methods to adhere to the labeling protocols.

At the same time, the present methods enable a reduction of the forcerequired for injection of the paliperidone palmitate extended releaseinjectable suspension from a syringe that has been maintained in asubstantially horizontal orientation during shipping of the syringe.Accordingly, the present disclosure embraces methods for reducing aforce required for injection of a paliperidone palmitate extendedrelease injectable suspension. For example, the force required forinjection from the syringe may be about 5-60% less than a force requiredfor injection of a paliperidone palmitate extended-release injectablesuspension from a syringe that was not maintained in a substantiallyhorizontal orientation during shipping of the syringe. The forcerequired for injection from the syringe may be, for example, about 5,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% less than a forcerequired for injection of a paliperidone palmitate extended-releaseinjectable suspension from a syringe that was not maintained in asubstantially horizontal orientation during shipping of the syringe. Insome embodiments, the force required for injection from the syringe maybe about 10-55, 15-50, 20-50, 25-45, or 30-40% less than a forcerequired for injection of a paliperidone palmitate extended-releaseinjectable suspension from a syringe that was not maintained in asubstantially horizontal orientation during shipping of the syringe. Inaddition, and at the same time, the present methods enable a reductionof the force required for injection of the paliperidone palmitateextended release injectable suspension from a syringe that has beenmaintained in an orientation during shipping that varies from theorientation of the syringe during pre-shipping storage, such as in asubstantially horizontal orientation during shipping of the syringe whenthe orientation during pre-shipping storage was not substantiallyhorizontal. Accordingly, the present disclosure embraces methods forreducing a force required for injection of a paliperidone palmitateextended release injectable suspension. For example, the force requiredfor injection from the syringe may be about 5-60% less than a forcerequired for injection of a paliperidone palmitate extended-releaseinjectable suspension from a syringe that was not maintained in anorientation during shipping that varies from the orientation of thesyringe during pre-shipping storage. The force required for injectionfrom the syringe may be, for example, about 5, 10, 15, 20, 25, 30, 35,40, 45, 50, 55, or 60% less than a force required for injection of apaliperidone palmitate extended-release injectable suspension from asyringe that was not maintained in an orientation during shipping thatvaries from the orientation of the syringe during pre-shipping storage.In some embodiments, the force required for injection from the syringemay be about 10-55, 15-50, 20-50, 25-45, or 30-40% less than a forcerequired for injection of a paliperidone palmitate extended-releaseinjectable suspension from a syringe that was not maintained in anorientation during shipping that varies from the orientation of thesyringe during pre-shipping storage.

In absolute terms, the force required for injection of the paliperidonepalmitate extended release injectable suspension from the syringe may beabout 10-25 Newtons less than a force required for injection of apaliperidone palmitate extended-release injectable suspension from asyringe that was not maintained in a substantially horizontalorientation during shipping of the syringe. The force required forinjection from the syringe may be, for example, about 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 Newtons less than aforce required for injection of a paliperidone palmitateextended-release injectable suspension from a syringe that was notmaintained in a substantially horizontal orientation during shipping ofthe syringe. The amount of force that is actually required for injectionof the paliperidone palmitate extended release injectable suspensionfrom the syringe may be, for example, about 10-25 Newtons. Thus, theforce required for injection from the syringe may be, for example, about10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25Newtons. In addition, in absolute terms, the force required forinjection of the paliperidone palmitate extended release injectablesuspension from the syringe may be about 5-25 Newtons less than a forcerequired for injection of a paliperidone palmitate extended-releaseinjectable suspension from a syringe that was not maintained in anorientation during shipping that varies from the orientation of thesyringe during pre-shipping storage. The force required for injectionfrom the syringe may be, for example, about 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 Newtons less thana force required for injection of a paliperidone palmitateextended-release injectable suspension from a syringe that was notmaintained in an orientation during shipping that varies from theorientation of the syringe during pre-shipping storage. The amount offorce that is actually required for injection of the paliperidonepalmitate extended release injectable suspension from the syringe maybe, for example, about 10-25 Newtons. Thus, the force required forinjection from the syringe may be, for example, about 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 Newtons.

The present methods may further comprise assessing the amount of forcethat is required to complete an injection of the paliperidone palmitateextended release injectable suspension from the syringe. The assessmentmay be performed using any available measurement technique.

The present methods may also or alternatively comprise assessing whetheran injection of the paliperidone palmitate extended-release injectablesuspension from the syringe is complete. The assessment may includemeasuring the amount of non-resuspended paliperidone palmitate withinthe tip of the syringe exceeds a certain value, such as, for example,about 4, 3.75, 3.5, 3.25, 3, 2.75, 2.5, 2.25, 2, 1.75, 1.5, 1.25, 1,0.75, 0.5, or 0.25 mm in length.

Also disclosed herein are methods for improving resuspendability of apaliperidone palmitate extended release injectable suspension within asyringe comprising maintaining the syringe in a substantially horizontalorientation during storage of the syringe. Storage of the syringe mayoccur prior to, or following, shipping of the syringe. In certainembodiments, the storage of the syringe occurs following shipping of thesyringe, e.g., at a location that corresponds to the health carefacility where administration of the paliperidone palmitate occurs.These methods may be performed independently from or in conjunction withthe above-described methods of improving resuspendability that comprisemaintaining the syringe in a substantially horizontal orientation duringshipping. In other words, the syringe may be stored in the substantiallyhorizontal orientation, shipped in the substantially horizontalorientation, or both shipped and stored in the substantially horizontalorientation. Storage of the syringe in a substantially horizontalorientation may be facilitated by markings or other instructions on thepackaging or container that houses the syringe, and such markings may bethe same as, or different from, markings or instructions that areintended to ensure maintenance of a substantially horizontal orientationduring shipping. As in the case of the methods comprising maintainingthe substantially horizontal orientation during shipping, the presentmethods may further comprise monitoring in order to ensure themaintenance of the substantially horizontal orientation during storage.Approaches for monitoring may be the same as those described above inconnection with the maintenance of the substantially horizontalorientation during shipping. Also disclosed herein are methods forimproving resuspendability of a paliperidone palmitate extended releaseinjectable suspension within a syringe comprising maintaining thesyringe in an orientation during shipping that varies from theorientation of the syringe during pre-shipping storage, such as in asubstantially horizontal orientation during storage of the syringe whenthe orientation during pre-shipping storage was not substantiallyhorizontal. Storage of the syringe may occur prior to, or following,shipping of the syringe. In certain embodiments, the storage of thesyringe occurs following shipping of the syringe, e.g., at a locationthat corresponds to the health care facility where administration of thepaliperidone palmitate occurs. These methods may be performedindependently from or in conjunction with the above-described methods ofimproving resuspendability that comprise maintaining the syringe in anorientation during shipping that varies from the orientation of thesyringe during pre-shipping storage. In other words, the syringe may beshipped in the substantially horizontal orientation, and subsequentlystored in the substantially horizontal orientation, or both shipped andstored in the substantially horizontal orientation. Storage of thesyringe in a particular orientation may be facilitated by markings orother instructions on the packaging or container that houses thesyringe, and such markings may be the same as, or different from,markings or instructions that are intended to ensure maintenance of adesired orientation during shipping. As in the case of the methodscomprising maintaining a particular orientation during shipping, thepresent methods may further comprise monitoring in order to ensure themaintenance of the desired orientation during storage. Approaches formonitoring may be the same as those described above in connection withthe maintenance of the desired orientation during shipping.

The present disclosure also provides a population of syringes thatrespectively contain paliperidone palmitate extended release injectablesuspension, wherein each of the syringes have been shipped to adestination, and the syringes were each maintained in a substantiallyhorizontal orientation during shipping of the syringe. Each member ofthe population of syringes will therefore accrue the benefits describedabove associated with shipping in a substantially horizontalorientation, including improved resuspendability, less residue in thesyringe tip following administration, less force required foradministration, and the like. The population of syringes may includeabout 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, 95, 100, 120, 140, 160, 180, 200, 225, 250, 275, 300, 325, 350, 375,400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300,1400, 1500, 1600, 1700, 1800, 1900, 2000, or more than 2000 individualsyringes. Each member of the population of syringes may include thesyringe types and paliperidone palmitate suspensions otherwise describedherein in accordance with the presently disclosed methods. In addition,the present disclosure also provides a population of syringes thatrespectively contain paliperidone palmitate extended release injectablesuspension, wherein each of the syringes have been shipped to adestination, and the syringes were each maintained in an orientationduring shipping that varies from the orientation of the syringe duringpre-shipping storage, such as in a substantially horizontal orientationduring shipping of the syringe when the orientation during pre-shippingstorage was not substantially horizontal. Each member of the populationof syringes will therefore accrue the benefits described aboveassociated with shipping in an orientation during shipping that variesfrom the orientation of the syringe during pre-shipping storage,including improved resuspendability, less residue in the syringe tipfollowing administration, less force required for administration, andthe like. The population of syringes may include about 5, 10, 15, 20,25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 120,140, 160, 180, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450,475, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600,1700, 1800, 1900, 2000, or more than 2000 individual syringes. Eachmember of the population of syringes may include the syringe types andpaliperidone palmitate suspensions otherwise described herein inaccordance with the presently disclosed methods.

Also provided herein are pharmaceutical products that comprise apaliperidone palmitate extended-release injectable suspension within asyringe for administration to a patient suffering from schizophrenia,wherein the syringe has undergone pre-shipping storage and has beenshipped, and wherein the syringe has been maintained in an orientationduring the shipping that varied from the orientation of the syringeduring pre-shipping storage. The respective characteristics of thepaliperidone palmitate extended-release injectable suspension, thesyringe, the pre-shipping storage conditions, the orientation of thesyringe during pre-shipping storage, the shipping conditions, and theorientation of the syringe during shipping may be in accordance with anyof the embodiments described above in connection with the inventivemethods for improving resuspendability of a paliperidone palmitateextended-release injectable suspension within a syringe and theinventive populations of syringes.

For example, the syringe may have been housed within a containercomprising an outer surface that included instructions for maintainingthe container during shipping in an orientation that corresponds to thedesired orientation of the syringe. In some embodiments, the syringe washoused within a container comprising an outer surface that includedmarkings that indicated an orientation of the container that correspondsto maintaining the desired orientation of the syringe.

Following the shipping, the syringe may contain no more than about 1.5mm or no more than about 1 mm of residue representing non-resuspendedpaliperidone palmitate after injection of the suspension. For example,the syringe may contain about 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8,0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm of residue representingnon-resuspended paliperidone palmitate after injection of thesuspension.

The paliperidone palmitate extended-release injectable suspension withinthe syringe may contain about 273, 410, 546, or 819 mg of paliperidonepalmitate. In other embodiments, the suspension contains about 1092 or1560 mg of paliperidone palmitate.

The shipping orientation may have varied from the orientation of thesyringe during pre-shipping storage by about 45 degrees to about 135degrees. For example, the orientation of the syringe during shipping mayhave varied from the orientation of the syringe during pre-shippingstorage by about 45, 50, 55, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,105, 110, 115, 120, 125, 130, or 135 degrees

In some embodiments of the presently disclosed pharmaceutical product,the pre-shipping storage orientation was tip down. In some embodimentsof the presently disclosed pharmaceutical product, the shippingorientation was substantially horizontal. In certain embodiments of thepresently disclosed pharmaceutical product, the pre-shipping storageorientation was tip down, and the shipping orientation was tip up orsubstantially horizontal. In other embodiments, the pre-shipping storageorientation was tip down, and the shipping orientation was substantiallyhorizontal. In other embodiments, the pre-shipping storage was tip down,and the shipping orientation was tip up.

The present disclosure also provides methods of treating schizophreniacomprising administering to a patient suffering from schizophrenia apaliperidone palmitate extended-release injectable suspension from asyringe, wherein the syringe has undergone pre-shipping storage and hasbeen shipped, and wherein the syringe was maintained in an orientationduring the shipping that varied from the orientation of the syringeduring pre-shipping storage. The present disclosure also provides apaliperidone palmitate extended-release injectable suspension for use inmethods of treating schizophrenia, wherein these methods compriseadministering to a patient suffering from schizophrenia the paliperidonepalmitate extended-release injectable suspension from a syringe, whereinthe syringe has undergone pre-shipping storage and has been shipped, andwherein the syringe was maintained in an orientation during the shippingthat varied from the orientation of the syringe during pre-shippingstorage. Administration of the suspension should be performed, forexample, in accordance with the protocols described on the label of theaforementioned commercially available paliperidone palmitate extendedrelease injectable suspension products. Although the present methodsmitigate certain instances of failure by health care personnel to adhereprecisely to the recommended steps prior to and during administration ofpaliperidone palmitate extended release injectable suspension, it isstill advisable for the administration of the suspension from thesyringe according to the present methods to adhere to the labelingprotocols.

With respect to the presently disclosed methods of treatingschizophrenia, the respective characteristics of the paliperidonepalmitate extended-release injectable suspension, the syringe, thepre-shipping storage conditions, the orientation of the syringe duringpre-shipping storage, the shipping conditions, and the orientation ofthe syringe during shipping may be in accordance with any of theembodiments described above in connection with the inventive methods forimproving resuspendability of a paliperidone palmitate extended-releaseinjectable suspension within a syringe and the inventive populations ofsyringes.

For example, the syringe may have been housed within a containercomprising an outer surface that included instructions for maintainingthe container during shipping in an orientation that corresponds to thedesired orientation of the syringe. In some embodiments, the syringe washoused within a container comprising an outer surface that includedmarkings that indicated an orientation of the container that correspondsto maintaining the desired orientation of the syringe.

Following the shipping, the syringe may contain no more than about 1.5mm or no more than about 1 mm of residue representing non-resuspendedpaliperidone palmitate after injection of the suspension. For example,the syringe may contain about 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8,0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm of residue representingnon-resuspended paliperidone palmitate after injection of thesuspension.

The paliperidone palmitate extended-release injectable suspension withinthe syringe may contain about 273, 410, 546, or 819 mg of paliperidonepalmitate. In other embodiments, the suspension contains about 1092 or1560 mg of paliperidone palmitate.

The shipping orientation may have varied from the orientation of thesyringe during pre-shipping storage by about 45 degrees to about 135degrees. For example, the orientation of the syringe during shipping mayhave varied from the orientation of the syringe during pre-shippingstorage by about 45, 50, 55, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,105, 110, 115, 120, 125, 130, or 135 degrees

In some embodiments of the presently disclosed methods of treatingschizophrenia, the pre-shipping storage orientation was tip down. Insome embodiments of the presently disclosed methods of treatingschizophrenia, the shipping orientation was substantially horizontal. Incertain embodiments of the presently disclosed methods, the pre-shippingstorage orientation was tip down, and the shipping orientation was tipup or substantially horizontal. In other embodiments, the pre-shippingstorage orientation was tip down, and the shipping orientation wassubstantially horizontal. In other embodiments, the pre-shipping storagewas tip down, and the shipping orientation was tip up.

The present disclosure also provides the use of a paliperidone palmitateextended-release injectable suspension in the manufacture of amedicament for treating schizophrenia, wherein the paliperidonepalmitate extended-release injectable suspension is prepared foradministration from a syringe, wherein the syringe has undergonepre-shipping storage and has been shipped, and wherein the syringe wasmaintained in an orientation during the shipping that varied from theorientation of the syringe during pre-shipping storage. Administrationof the suspension should be performed, for example, in accordance withthe protocols described on the label of the aforementioned commerciallyavailable paliperidone palmitate extended release injectable suspensionproducts. Although the present uses mitigate certain instances offailure by health care personnel to adhere precisely to the recommendedsteps prior to and during administration of paliperidone palmitateextended release injectable suspension, it is still advisable for theadministration of the suspension from the syringe according to thepresent uses to adhere to the labeling protocols.

With respect to the presently disclosed uses, the respectivecharacteristics of the paliperidone palmitate extended-releaseinjectable suspension, the syringe, the pre-shipping storage conditions,the orientation of the syringe during pre-shipping storage, the shippingconditions, and the orientation of the syringe during shipping may be inaccordance with any of the embodiments described above in connectionwith the inventive methods for improving resuspendability of apaliperidone palmitate extended-release injectable suspension within asyringe and the inventive populations of syringes.

For example, the syringe may have been housed within a containercomprising an outer surface that included instructions for maintainingthe container during shipping in an orientation that corresponds to thedesired orientation of the syringe. In some embodiments, the syringe washoused within a container comprising an outer surface that includedmarkings that indicated an orientation of the container that correspondsto maintaining the desired orientation of the syringe.

Following the shipping, the syringe may contain no more than about 1.5mm or no more than about 1 mm of residue representing non-resuspendedpaliperidone palmitate after injection of the suspension. For example,the syringe may contain about 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8,0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm of residue representingnon-resuspended paliperidone palmitate after injection of thesuspension.

The paliperidone palmitate extended-release injectable suspension withinthe syringe may contain about 273, 410, 546, or 819 mg of paliperidonepalmitate. In other embodiments, the suspension contains about 1092 or1560 mg of paliperidone palmitate.

The shipping orientation may have varied from the orientation of thesyringe during pre-shipping storage by about 45 degrees to about 135degrees. For example, the orientation of the syringe during shipping mayhave varied from the orientation of the syringe during pre-shippingstorage by about 45, 50, 55, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,105, 110, 115, 120, 125, 130, or 135 degrees

In some embodiments of the presently disclosed uses, the pre-shippingstorage orientation was tip down. In some embodiments of the presentlydisclosed uses, the shipping orientation was substantially horizontal.In certain embodiments of the presently disclosed uses, the pre-shippingstorage orientation was tip down, and the shipping orientation was tipup or substantially horizontal. In other embodiments, the pre-shippingstorage orientation was tip down, and the shipping orientation wassubstantially horizontal.

In other embodiments, the pre-shipping storage was tip down, and theshipping orientation was tip up.

The invention is further defined with reference to the followingnumbered clauses:

-   1. A method for improving resuspendability of a paliperidone    palmitate extended-release injectable suspension within a syringe    comprising maintaining the syringe in a substantially horizontal    orientation during shipping of the syringe.-   2. The method according to clause 1, wherein maintaining the syringe    in the substantially horizontal orientation comprises loading the    syringe onto a shipping vehicle in the substantially horizontal    orientation, monitoring the syringe during shipping to confirm    maintenance of the substantially horizontal orientation, or both.-   3. The method according to clause 1 or clause 2, further comprising    housing the syringe within a container comprising an outer surface    that bears instructions for maintaining the container during    shipping in an orientation that corresponds to the orientation of    the syringe that is substantially horizontal.-   4. The method according to any preceding clause, further comprising    housing the syringe within a container comprising an outer surface    that bears markings that indicate an orientation of the container    that corresponds to maintaining the orientation of the syringe that    is substantially horizontal.-   5. The method according to any preceding clause, further comprising,    subsequent to shipping of the syringe, maintaining the syringe at a    storage location in a substantially horizontal orientation.-   6. The method according to any preceding clause, wherein the syringe    is shipped by airplane, truck, boat, or railroad.-   7. The method according to any preceding clause, wherein, following    the shipping, the syringe contains no more than about 1.5 mm of    residue representing non-resuspended paliperidone palmitate after    administration.-   8. The method according to any preceding clause, wherein, following    the shipping, the syringe contains no more than about 1 mm of    residue representing non-resuspended paliperidone palmitate.-   9. The method according to any preceding clause, wherein the syringe    has a capacity of 1 mL, 2.25 mL, 2.8 mL, or 3 mL and includes a 22    gauge needle that is 1 or 1.5 inches long.-   10. The method according to any one of clauses 1-Error! Reference    source not found., wherein the syringe has a capacity of 5 mL, and    includes a 20 gauge needle that is 1.5 inches long.-   11. The method according to any one of clauses 1-Error! Reference    source not found., wherein the suspension contains about 273, 410,    546, or 819 mg of paliperidone palmitate.-   12. The method according to any one of clauses 1-Error! Reference    source not found., wherein the suspension contains about 1092 or    1560 mg of paliperidone palmitate.-   13. The method according to any one of clauses 1-Error! Reference    source not found., further comprising administering the suspension    from the syringe to a patient.-   14. A method for reducing a force required for injection of a    paliperidone palmitate extended-release injectable suspension from a    syringe comprising maintaining the syringe in a substantially    horizontal orientation during shipping of the syringe.-   15. The method according to clause 14, wherein the force required    for injection from the syringe is about 20% to about 50% less than a    force required for injection of a paliperidone palmitate    extended-release injectable suspension from a syringe that was not    maintained in a substantially horizontal orientation during shipping    of the syringe.-   16. The method according to 14 or clause 15, wherein the force    required for injection from the syringe is about 10-25 Newtons less    than a force required for injection of a paliperidone palmitate    extended-release injectable suspension from a syringe that was not    maintained in a substantially horizontal orientation during shipping    of the syringe.-   17. The method according to any one of clauses 14-16, wherein the    force required for injection from the syringe is about 10-25    Newtons.-   18. The method according to any one of clauses 14-17, further    comprising assessing the force required to complete an injection of    the paliperidone palmitate extended-release injectable suspension    from the syringe.-   19. A method for reducing the likelihood of incomplete injection of    a paliperidone palmitate extended-release injectable suspension from    a syringe comprising maintaining the syringe in a substantially    horizontal orientation during shipping of the syringe.-   20. The method according to clause 19, further comprising assessing    whether an injection of the paliperidone palmitate extended-release    injectable suspension from the syringe is complete.-   21. A method for improving resuspendability of a paliperidone    palmitate extended-release injectable suspension within a syringe    comprising maintaining the syringe in a substantially horizontal    orientation during storage of the syringe.-   22. The method according to clause 21, wherein said storage occurs    following shipping of the syringe.-   23. A population of syringes that respectively contain paliperidone    palmitate extended release injectable suspension, wherein each of    the syringes have been shipped to a destination, and the syringes    were each maintained in a substantially horizontal orientation    during shipping of the syringe.-   24. The population according to clause 23, comprising at least 100    individual syringes

EXAMPLES

The present invention is further defined in the following Examples. Itshould be understood that these examples, while indicating preferredembodiments of the invention, are given by way of illustration only, andshould not be construed as limiting the appended claims From the abovediscussion and these examples, one skilled in the art can ascertain theessential characteristics of this invention, and without departing fromthe spirit and scope thereof, can make various changes and modificationsof the invention to adapt it to various usages and conditions. Unlessotherwise noted, references to PP6M in the examples refer to theformulation in Example 2.

Example 1—Three Month Extended Release Formulation (PP3M)

Table 1 below includes an exemplary three-month extended releaseformulation (PP3M) of 200 mg/mL eq. paliperidone suitable forintramuscular (IM) injection.

TABLE 1 PP3M Component Concentration (mg/mL) Paliperidone Palmitate 312Polysorbate 20 10 Polyethylene Glycol 4000 75 Citric Acid Monohydrate7.5 Sodium Dihydrogen Phosphate Monohydrate 6 Sodium Hydroxide 5.4 Waterfor Injection q.s. ad 1 mL

The PP3M can be provided in a prefilled syringe, with dosage strengthsranging from 175 mg eq. to 525 mg eq. obtained by filling the syringeswith different volumes of a 200 mg/mL eq. bulk suspension. Table 2 showsthe different dosage strengths, including syringe size, and nominal fillvolume.

TABLE 2 PP3M Dosage Strengths with Syringe Size and Fill Volume Dose asPaliperidone Dose Equivalent Nominal Palmitate as Paliperidone SyringeFill Volume (mg) (mg) Size (mL) 273 175 1 mL Long 0.875 410 263 2.25 mL1.315 546 350 2.25 mL 1.750 819 525 2.8 mL 2.625

Table 3 describes the syringe components used to package the Pp 3m.

TABLE 3 Syringe Components for PP3M Component Description Syringe BarrelTransparent Cyclic Olefin Copolymer (COC) with Integrated Luer LockSizes of 1 mL Long, 2.25 mL or 2.8 mL Tip Cap Bromobutyl Rubber, DarkGrey Plunger Stopper FluroTec © Coated Bromobutyl Rubber, Dark Grey (1mL Long used for 1 mL Long syringe; and 1-3 mL used for 2.25 mL syringeand 2.8 mL syringe)

Example 2—Six Month Extended Release Formulation (PP6M)

Table 4 below includes an exemplary six-month extended releaseformulation (PP6M) of 200 mg/mL eq. paliperidone palmitate suitable forintramuscular (IM) injection.

TABLE 4 PP6M Unit Dose Unit Dose Concentration (mg/syringe in(mg/syringe in Component (mg/mL) 3.5 mL Dose) 5.0 mL Dose) Paliperidone312 1092 1560 Palmitate Polysorbate 20 10 35 50 Polyethylene 75 262.5375 Glycol 4000 Citric Acid 7.5 26.25 37.5 Monohydrate Sodium Dihydrogen6 21 30 Phosphate Monohydrate Sodium Hydroxide 5.4 18.9 27 Water forInjection q.s. ad 1.0 mL q.s. ad 3.5 mL q.s. ad 5.0 mL

The PP6M can be provided in a prefilled syringe, with dosage strengthsranging from 700 mg eq. to 1000 mg eq. obtained by filling the syringes,with different volumes of a 200 mg/mL eq. bulk suspension. Table 5 showsthe different dosage strengths, including syringe size, and nominal fillvolume.

TABLE 5 PP6M Dosage Strengths with Syringe Size and Fill Volume Dose asPaliperidone Dose Equivalent Nominal Palmitate as Paliperidone SyringeFill Volume (mg) (mg) Size (mL) 1092 700 5 mL 3.5 1560 1000 5 mL 5.0

Table 6 describes the syringe components used to package the six-monthextended release formulation.

TABLE 6 Syringe Components for PP6M Component Description Syringe BarrelTransparent Cyclic Olefin Copolymer (COC) with Integrated Luer Lock TipCap Bromobutyl Rubber Plunger Stopper Bromobutyl Rubber Plunger RodPolypropylene Backstop (aka Homopolypropylene Finger Flange)

Example 3—Storage Conditions Prior to Shipping

Stability studies were performed with process performance qualification(PPQ) batches of PP6M in five different orientations prior to shipping:horizontal, tip down +45 degrees, tip up −45 degrees, tip down +45degrees and tip down −45 degrees. The following test results wereobtained with respect to syringes that were stored followingmanufacture, but that were not shipped prior to testing. Sensor testingwith 5 seconds of shaking was performed at two different temperatures:25° C. and 30° C. The results from this experiment are provided in Table7:

TABLE 7 PPQ I PPQ II PPQ III 3.5 ml fill 5 ml fill 3.5 ml fill 5 ml fill3.5 ml fill 5 ml fill HORIZONTAL 9 M 25° C. 0 0 0 0 0 1 mm 9 M 30° C. 00 0 0 2 mm 2 mm, 2 mm TIP UP 9 M 25° C. 0 0 0 0 0 1 mm (blister: ↑) 9 M30° C. 0 0 0 0 0 0 TIP UP 9 M 25° C. NT NT NT NT NT 0 (blister: 

) 9 M 30° C. NT NT NT NT NT 0 TIP DOWN 9 M 25° C. 0 1 mm 0 2 mm NT 0(blister: ↓) 9 M 30° C. 0 0 0 1 mm, NT 0 2 mm TIP DOWN 9 M 25° C. NT NTNT NT NT 0 (blister: 

) 9 M 30° C. NT NT NT NT NT 0 Note: PPQ III horizontal samples areblistered (housed in a blister package), PPQII and PPQI horizontalsamples are not blistered. 9 M = nine month storage period. NT = nottested.

Injectability testing was performed via manual injection, using a sensoron the thumb pad of the plunger rod to record force (Newton) over time(seconds). Force injection profiles for the samples in PPQ I and PPQ IIafter 5 seconds of vigorous shaking are illustrated in FIGS. 1A-1F.

The results suggested that product stored in any position prior toshipping could be resuspended with a normal amount of force, i.e., thatthe force required to expel syringe contents was not related to thestorage position before shipping occurs. The different storage positionsgive comparable results indicating that the position in which thesyringe is stored prior to shipping is not critical when shaken for atleast 5 seconds. Complete injection could be performed with acceptableinjection forces.

After this experiment, it became apparent that the storage position ofthe product during stability testing and prior to shipping was not animportant determinant of resuspendability. As described below in Example4, it was found that the shipment orientation was much more importantthan pre-shipping storage orientation.

Example 4—Orientation During Simulated Shipping

Following a period of storage in a tip down orientation at themanufacturing facility, syringes containing the PP6M formulation weresubjected to a simulated shipping experiment with vibrationscorresponding to Level I and Level II vibrations as defined by ASTMD4169-16 for simulated air shipments. These are the highest levels ofvibration during air shipment and exceed vibration levels defined forshipments by truck. The resuspendability and injectability of the PP6Mformulation after the simulated shipment was tested with no or only 5seconds of shaking (shorter than defined by instructions for use (IFU),which are consistent with the instructions provided on the label for theINVEGA TRINZA® (PP3M product), IFU for PP6M is 2×15 seconds of shaking,and IFU for PP3M Is 1×15 seconds of shaking)) to increase thesensitivity of the test of detecting differences. A summary of theresidue leftover in the syringes, and the maximum force required toempty the syringes to that point are provided below in Table 8:

TABLE 8 Residue after Preparations According to Instructions for Use(With Pull Back and Deaeration) Position Resusp. 2 hours level II 2h(II) + 3 hours (I) Tip down NO shaking 2 mm (36N) 16 mm (40N) Cannot beinj. (49N) 14 mm (37N) 5° shaking 1 mm (35N) 1 mm (32N) (4 shakes/s) 3mm (18N) 1 mm (30N) 1 mm (26N) 1 mm (36N) Horizontal NO shaking 0 mm(26N) 0 mm (34N) 0 mm (26N) 0 mm (29N) 5° shaking 0 mm (17N) 0 mm (19N)(4 shakes/s) 0 mm (16N) 0 mm (17N) 3 mm (18N) 0 mm (17N)

FIGS. 2A-2D provide injection force curves for syringes subjected tovibration experiments while in a horizontal or tip down orientation.Injectability testing was performed via manual injection, using a sensoron the thumb pad of the plunger rod to record force (Newton) over time(seconds). The vibration conditions included two hours of Level IIsimulated air shipment and three hours of Level I simulated air shipmentin accordance with ASTM D4169. FIG. 2A corresponds to a syringe that wasin the tip down orientation and was not subjected to shaking priorinjection. FIG. 2B corresponds to a syringe that was in the tip downorientation and was subjected to five seconds of shaking prior toinjection. FIG. 2C corresponds to a syringe that was in a horizontalorientation and was not subjected to shaking prior to injection. FIG. 2Dcorresponds to a syringe that was in a horizontal orientation and wassubjected to five seconds of shaking prior to injection.

The results from this experiment confirm that shipment of syringes inthe tip-down position following storage in a tip-down orientation canresult in the requirement for very high forces in order to expresssyringe contents, and that the contents of such syringes are notcompletely resuspended after 5 seconds of shaking. As a practicalmatter, health care providers will not be pushing up to 30 or 35N,especially when injecting a patient.

However, when syringes were shipped in the horizontal manner afterhaving been stored in a tip-down orientation, injection forces were inthe range of 10-20 Newtons, indicating that the product required lessshaking for good resuspension to occur. By comparison, the forcesrequired to expel a one-month paliperidone palmitate injectablesuspension, which represents a much less concentrated formulation (andthereby a preparation that is much less vulnerable to impaction andthereby having lower resuspension requirements) are in the range of 7-12Newtons.

Example 5—Varying Orientation of Syringes During Shipping Relative toOrientation During Pre-Shipping Storage Reduces Injection Forces andPost-Injection Residue

After initial proof that horizontal orientation of PP6M syringes duringshipment leads to improved resuspendability and injectability propertiescompared to tip down orientation a further study was initiated to assessmore in depth the potential impact of different types and duration ofshipment and to monitor the behavior of PP6M syringes up to three monthsafter simulated shipment.

For this study, 5 mL syringes PP6M were selected from stabilitychambers. The 5 mL fill was chosen over the 3.5 mL fill as worst casefor resuspendability because of the higher product load in same 5 mLsyringe.

Before being exposed to simulated shipment conditions, samples from thedifferent batches, stored in different orientations in the stabilitychambers but not yet subjected to shipping conditions, were tested forresuspendability/injectability by manually injecting the syringe into acontainer after 5 seconds poorly shaking. The injectability forces wererecorded with a sensor attached to the thumb pad, and the height of theresidual product in the syringe was measured. All samples resulted incomplete injections with no or an acceptable product residue in thesyringe, concluding that the different pre-shipping storage orientationset-ups did not by themselves influence the properties of thesuspension, and that the product was easily resuspendable and injectableafter 9 months of storage.

Following this initial testing, syringes were transported by car fromBeerse, Belgium to a testing facility in Diepenbeek, Belgium andsubjected to different shipping simulations ranging from light exposure(lh truck light) to heavy exposure (4h air high). Simulated ship testingwas performed per ASTM D4169-16. During these shipping simulations, thesyringes were positioned either horizontally or tip down. During routinemanufacturing, the syringes are stored tip down in tubs after fillingtypically for a month or more. When a packaging order is issued, thesyringes are packed in blister kit and shipped after release. Within aday after the shipping simulation, samples exposed to the differentsimulated shipping conditions in different orientations were resuspendedby rapid shaking for 5 seconds and manually injecting the product into acontainer, while injection forces were measured with a sensor attachedto the thumb pad of the syringe. A shorter time to resuspend the product(5 s instead of 2×15 seconds per IFU) was used for the analysis toincrease the sensitivity of the test.

The rest of the syringes was stored horizontally or tip down as per theprotocol and the resuspendability/injectability of the syringes wasfurther assessed after one month, two months, or three months ofstorage.

As also described below, the analysis showed that the orientation of thesyringe before shipment relative to the shipping orientation, is animportant factor in the resuspension of the product.

In both single shipments and combined truck/air shipments, maintainingthe same orientation of the syringes during initial storage and shipmentled to more difficult to resuspend syringes resulting in more residualproduct after only 5 seconds of rapid shaking.

Storage position after shipment and storage time represented factorswith only limited impact on the resuspendability of the product.

The data provided in Tables 9-11, infra, demonstrate that when syringesare shipped horizontally following horizontal storage prior to shipping,there is more residual product after 5 seconds of rapid resuspendabilityand injection, compared to syringes that were stored tip down.

Similarly, syringes stored tip up before shipping and orientated tipdown during shipping contained no or very limited residual product after5 seconds of rapid resuspendability and injection.

In both single shipments and combined shipments, maintaining the sameorientation of the syringes during initial storage and shipment leads tosyringes that are more difficult to resuspend, resulting in moreresidual product after 5 seconds of rapid resuspendability and manualinjection.

Tables 9-11 provide the results for sets of samples and permit head tohead comparison between syringes for which orientation between initialstorage varied from that during shipment, as compared with syringes thatremained in the same orientation during pre-shipping storage andshipment.

Experiments 1 and 2 represent two data sets from testing that involved asingle type of simulated shipping, while Experiment 3 provides data fromthe combined shipping test (i.e., simulated air shipment followed by asimulated truck shipment).

TABLE 9 Experiment 1: Advantage of changes in orientation between preshipping storage and shipping Results after 5″ rapid shaking 1 day 3weeks 2 months 3 months Injec- Injec- Injec- Injec- Initial tion tiontion tion storage Shipping Shipping Storage Residue forces Residueforces Residue forces Residue forces Batch orientation orientation typeposition (mm) (N) (mm) (N) (mm) (N) (mm) (N) JHBOE Horizontal HorizontalAir 1 h Horizontal 1 43 8 55 4 53 2 46 low level JHBOE HorizontalHorizontal Air 1 h Horizontal 4 57 4 53 low level Average JHBOEHorizontal Horizontal Air 1 h Horizontal 1 43 8 55 4 55 3 51 low levelJHB53 Tip Up Horizontal Air 1 h Horizontal 0 26 0 41 0 38 0 50 low levelJHB53 Tip Up Horizontal Air 1 h Horizontal 0 35 0 30 low level AverageJHB53 Tip Up Horizontal Air 1 h Horizontal 0 25 0 55 0 37 0 40 low levelBenefit 100% 40% 100% 0% 100% 33% 100% 22%

TABLE 10 Experiment 2: Advantage of change in orientation betweenpre-shipping storage and shipping. Change in orientation betweenshipping and long term storage lesser effect Results after 5″ rapidshaking 1 day 3 weeks 2 months 3 months Injec- Injec- Injec- Injec-Initial tion tion tion tion storage Shipping Shipping Storage Residueforces Residue forces Residue forces Residue forces Batch orientationorientation type position (mm) (N) (mm) (N) (mm) (N) (mm) (N) JHBOE TipUp Horizontal Air 4 h Horizontal 0 21 0 50 0 40 0 35 high level JHBOETip Up Horizontal Air 4 h Horizontal 0 35 0 48 high level JHB10 Tip UpHorizontal Air 4 h Horizontal 0 22 0 41 0 33 3 52 high level JHB10 TipUp Horizontal Air 4 h Horizontal 0 31 0 28 high level Average JHB10 TipUp Horizontal Air 4 h Horizontal 0 22 0 46 0 35 1 41 high level JHBOETip Up Horizontal Air 4 h Tip Down 0 26 0 30 0 30 0 34 high level JHBOETip Up Horizontal Air 4 h Tip Down 0 33 0 34 high level JHB10 Tip UpHorizontal Air 4 h Tip Down 0 24 0 23 0 33 0 32 high level JHB10 Tip UpHorizontal Air 4 h Tip Down 0 32 0 33 high level Average JHB10 Tip UpHorizontal Air 4 h Tip Down 0 25 0 27 0 32 0 33 high level Average TipUp Horizontal Air 4 h Hor/Tip 0 23 0 36 0 33 0 37 high level down JEB5FTip Down Tip Down Air 4 h Horizontal 1 47 1 52 1 48 0 46 high levelJEB5F Tip Down Tip Down Air 4 h Horizontal 2 50 0 49 high level JEB5FTip Down Tip Down Air 4 h Horizontal 1 45 2 52 0 43 0 40 high levelJEB5F Tip Down Tip Down Air 4 h Horizontal 0 43 1 57 high level AverageJEB5F Tip Down Tip Down Air 4 h Horizontal 1 46 2 52 1 46 0 48 highlevel JEB5F Tip Down Tip Down Air 4 h Tip Down 2 45 5 56 2 51 3 50 highlevel JEB5F Tip Down Tip Down Air 4 h Tip Down 3 49 4 54 high levelJEB5F Tip Down Tip Down Air 4 h Tip Down 1 55 4 50 2 53 7 55 high levelJEB5F Tip Down Tip Down Air 4 h Tip Down 3 56 5 53 high level AverageJEB5F Tip Down Tip Down Air 4 h Tip Down 1 50 5 53 3 52 5 53 high levelAverage Tip Down Tip Down Air 4 h Hor/Tip 1 48 3 53 2 49 3 51 high leveldown Benefit 100% 52% 100% 31% 100% 32% 85% 27%

TABLE 11 Experiment 3: Advantage of changes in orientation between preshipping storage and shipping Results after 5″ rapid shaking 1 day 3weeks 2 months Initial Ship- Ship- Ship- Ship- Injec- Injec- Injec-storage ping ping ping ping tion tion tion orien- orien- type orien-type Storage Residue forces Residue forces Residue forces Batch tationtation 1 1 tation 2 2 position (mm) (N) (mm) (N) (mm) (N) JHB53 Hori-Hori- Air 2 h Hori- Truck Hori- 5 55 6 57 4 51 zontal zontal mediumzontal 4 h zontal level high JHB53 Hori- Hori- Air 2 h Hori- Truck Hori-4 66 6 56 zontal zontal medium zontal 4 h zontal level high JHB53 Hori-Hori- Air 2 h Hori- Truck Hori- 5 55 5 62 5 54 zontal zontal mediumzontal 4 h zontal level high JHB53 Tip Hori- Air 2 h Hori- Truck Hori- 242 0 36 4 54 Down zontal medium zontal 4 h zontal level high JHB53 TipHori- Air 2 h Hori- Truck Hori- 0 37 0 47 Down zontal medium zontal 4 hzontal level high JHB53 Tip Hori- Air 2 h Hori- Truck Hori- 2 42 0 37 251 Down zontal medium zontal 4 h zontal level high Benefit 60% 24% 100%41% 60% 6%

These data demonstrated that syringes shipped in an orientation thatvaried from the orientation during storage prior to shipment were easierto resuspend than syringes that were maintained in an orientation duringshipping that did not vary from the pre-shipping storage orientation.

What is claimed:
 1. A population of syringes that respectively containpaliperidone palmitate extended release injectable suspension, whereineach of the syringes have been stored prior to shipping and shipped to adestination, and the syringes were each maintained in a desiredorientation during shipping of the syringe that varies from theorientation of the syringe during pre-shipping storage.
 2. Thepopulation according to claim 1, comprising at least 100 individualsyringes.
 3. A pharmaceutical product comprising a paliperidonepalmitate extended-release injectable suspension within a syringe foradministration to a patient suffering from schizophrenia, wherein thesyringe has undergone pre-shipping storage and has been shipped, andwherein the syringe has been maintained in an orientation during theshipping that varies from the orientation of the syringe duringpre-shipping storage.
 4. The pharmaceutical product according to claim3, wherein the syringe was housed within a container comprising an outersurface that included instructions for maintaining the container duringshipping in an orientation that corresponds to the desired orientationof the syringe, that bears markings that indicate an orientation of thecontainer that corresponds to maintaining the desired orientation, orboth.
 5. The pharmaceutical product according to claim 3, wherein,following the shipping, the syringe contains no more than about 1.5 mmof residue representing non-resuspended paliperidone palmitate afterinjection of the suspension.
 6. The pharmaceutical product according toclaim 3, wherein the suspension contains about 273, 410, 546, or 819 mgof paliperidone palmitate.
 7. The pharmaceutical product according toclaim 3, wherein the suspension contains about 1092 or 1560 mg ofpaliperidone palmitate.
 8. The pharmaceutical product according to claim3, wherein the shipping orientation varied from the orientation of thesyringe during pre-shipping storage by about 45 degrees to about 135degrees.
 9. The pharmaceutical product according to claim 3, wherein thepre-shipping storage orientation was tip down, and the shippingorientation is tip up or substantially horizontal.
 10. Thepharmaceutical product according to claim 3, wherein the pre-shippingstorage orientation was tip down, and the shipping orientation issubstantially horizontal.
 11. The pharmaceutical product according toclaim 3, wherein the pre-shipping storage orientation of the syringe wastip-down.